Delirium, blood biomarkers for neurodegeneration, and dementia
Authors: Vincent Planche
Journal: The Lancet Healthy Longevity (2023)

I teach several times a year at medical school about delirium and dementia. I always start with a quick clinical case presenting a woman who is an octogenarian at the accident and emergency department of a hospital with temporospatial disorientation and delusions. I ask the students whether they think this person has delirium or dementia. Making conclusions at this time is impossible as delirium and dementia, which are distinct clinical syndromes, share similar symptoms, but I want to test their clinical reasoning. Delirium is an acute, transient, and curable medical emergency, whereas dementia is a slowly progressive condition. Moreover, dementia involves brain damage, whereas the cause of delirium is generally extraneurological in older people (eg, pain, sepsis, iatrogenesis, dehydration, acute urinary retention, or metabolic pathology). In short, delirium and dementia have nothing to do with each other. However, the experienced clinician should remember that the onset of a neurodegenerative process can lower the threshold for delirium occurrence, that delirium can initiate a series of events leading to functional decline,1Fong TG Tulebaev SR Inouye SK Delirium in elderly adults: diagnosis, prevention and treatment.Nat Rev Neurol. 2009; 5: 210-220Crossref PubMed Scopus (652) Google Scholar and that recurrent delirium might be the clinical manifestation of prodromal dementia with Lewy bodies, for example.2McKeith IG Ferman TJ Thomas AJ et al.Research criteria for the diagnosis of prodromal dementia with Lewy bodies.Neurology. 2020; 94: 743-755Crossref PubMed Scopus (334) Google Scholar The Article reported in this issue of The Lancet Healthy Longevity by Krogseth and colleagues3Krogseth M Davis D Jackson TA et al.Delirium, neurofilament light chain, and progressive cognitive impairment: analysis of a prospective Norwegian population-based cohort.Lancet Healthy Longev. 2023; (published online July 14.)https://doi.org/10.1016/S2666-7568(23)00098-3Summary Full Text Full Text PDF Scopus (6) Google Scholar will make me change my message next autumn. A previous meta-analysis reported that delirium was associated with long-term cognitive decline in patients who were surgical and non-surgical.4Goldberg TE Chen C Wang Y et al.Association of delirium with long-term cognitive decline: a meta-analysis.JAMA Neurol. 2020; 77: 1373-1381Crossref PubMed Scopus (214) Google Scholar Moreover, a previous cross-sectional study in patients undergoing surgery showed that delirium was associated with increased blood levels of neurofilament light chain (NfL; a marker of neuroaxonal injury) independent of inflammation.5Casey CP Lindroth H Mohanty R et al.Postoperative delirium is associated with increased plasma neurofilament light.Brain. 2020; 143: 47-54Crossref PubMed Scopus (94) Google Scholar However, the evidence remained limited to support a mechanistic relationship between delirium, neurodegeneration, and subsequent cognitive decline. Using a population-based cohort of people aged 65 years or older living in Norway who were receiving domiciliary care services at least once per week, Krogseth and colleagues have provided novel information about this relationship thanks to a dedicated mediation analysis of available longitudinal data. They showed independent pathways from baseline Montreal Cognitive Assessment (MoCA) score and baseline NfL to follow-up MoCA score with contributions from incident delirium and acute NfL levels. The largest cognitive decline after delirium was observed in people with better cognition in the previous 6 months, suggesting that this occurrence is particularly harmful to people without dementia. The Article by Krogseth and colleagues therefore reveals new information regarding the multifactorial pathophysiological mechanisms triggering neurodegeneration. The study constitutes a basis for encouraging the prevention of delirium, whatever its cause, to decrease the incidence of dementia in older people because delirium prevention could be a neuroprotective strategy. Although textbooks usually report dementia as a risk marker for delirium,1Fong TG Tulebaev SR Inouye SK Delirium in elderly adults: diagnosis, prevention and treatment.Nat Rev Neurol. 2009; 5: 210-220Crossref PubMed Scopus (652) Google Scholar delirium might be a risk factor for dementia via neuroaxonal damage. Delirium might trigger irreversible structural brain defects and not just transient functional impairment mediated by inflammation, disruption of neurotransmission, or acute stress responses.1Fong TG Tulebaev SR Inouye SK Delirium in elderly adults: diagnosis, prevention and treatment.Nat Rev Neurol. 2009; 5: 210-220Crossref PubMed Scopus (652) Google Scholar I am going to have to change my key messages to students next autumn. Krogseth and colleagues advisedly used blood NfL in their study without seeking to develop novel dementia risk prediction models, combining delirium occurrence and NfL levels in people aged 65 years or older. Blood NfL is used only to answer epidemiological and pathophysiological questions. Overinterpretation of their findings would lead to misuse of blood NfL in clinical practice. Presupposing that 50% of delirium cases would be undiagnosed during admission to or treatment in hospital, some researchers and clinicians call for developing biomarkers for delirium.6Dunne SS Coffey JC Konje S et al.Biomarkers in delirium: a systematic review.J Psychosom Res. 2021; 147110530Crossref PubMed Scopus (29) Google Scholar However, biomarkers for neurodegeneration should not be used in people for whom there is no clinical evidence of an underlying neurodegenerative disease because they are less performant than simple clinical variables to predict future dementia in older adults who are cognitively unimpaired.7Planche V Bouteloup V Pellegrin I et al.Validity and performance of blood biomarkers for Alzheimer disease to predict dementia risk in a large clinic-based cohort.Neurology. 2023; 100: e473-e484Crossref PubMed Scopus (17) Google Scholar Delirium should remain a clinical syndrome as defined in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition. Returning to the clinical case initially presented in this Comment, blood NfL levels will not contribute anything to the diagnosis and management of this person as they might be increased in delirium as well as in dementia, and they will not inform us about the underlying cause to be treated. Furthermore, typical blood NfL concentration increases non-linearly after age 60 years,8Khalil M Pirpamer L Hofer E et al.Serum neurofilament light levels in normal aging and their association with morphologic brain changes.Nat Commun. 2020; 11: 812Crossref PubMed Scopus (295) Google Scholar so individual interpretation in older people is almost impossible. In this clinical case, I encourage my students to pick up the telephone and call the family to find out what the person's usual cognitive functioning is. Clinical examination should continue to take precedence over paraclinical tests, even in the age of blood biomarkers for neurodegenerative diseases The measure of blood NfL in epidemiological studies highlights the neurodegenerative effects of any delirium event in older adults and its link with future cognitive decline. These findings should not be overinterpreted for diagnostic or prognostic purposes as they would negatively affect clinical practice. In neurodegenerative diseases, biomarkers of any kind should not be used without an evocative clinical presentation, as recommended for the early diagnosis of Alzheimer's disease.9Dubois B Villain N Frisoni GB et al.Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group.Lancet Neurol. 2021; 20: 484-496Summary Full Text Full Text PDF PubMed Scopus (367) Google Scholar Blood NfL is not the neurogeriatrician's troponin to investigate delirium. On this subject, I won't be changing anything in my course next autumn. I declare no competing interests. Delirium, neurofilament light chain, and progressive cognitive impairment: analysis of a prospective Norwegian population-based cohortIn people aged 65 years or older, an episode of delirium was associated with a decline in MoCA score. Greater neuronal injury during acute illness and delirium, measured by NfL, was associated with greater cognitive decline. For clinicians, our finding of delirium associated with both signs of acute neuronal injury, measured via NfL, and cognitive decline is important regarding the risk of long-term cognitive deterioration and to acknowledge that delirium is harmful for the brain. Full-Text PDF Open Access